Piperidinesulfonylurea derivatives

ABSTRACT

A series of novel 1-piperidinesulfonylurea compounds derived from a pyrimidine monocarboxylic acid have been prepared by reacting an appropriate sulfamide with an organic isocyanate or a trisubstituted urea equivalent thereof. The sulfamylureas so obtained are useful in therapy as oral hypoglycemic agents. Typical members include those compounds derived from 1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylic acid, of which 1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea is a most preferred embodiment.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 629,771 filedNov. 7, 1975 now U.S. Pat. No. 3,998,828 which is a division ofapplication Ser. No. 546,003 filed Jan. 31, 1975 now U.S. Pat. No.3,936,445.

BACKGROUND OF THE INVENTION

This invention relates to new and useful sulfamylurea derivatives, whichare effective in reducing blood sugar levels to a remarkably highdegree. More particularly, it is concerned with certain novel4-substituted-1-piperidinesulfonylureas and their base salts withpharmacologically acceptable cations, which are useful in therapy asoral hypoglycemic agents for the treatment of diabetes.

In the past, various attempts have been made by numerous investigatorsin the field of organic medicinal chemistry to obtain new and betteroral hypoglycemic agents. For the most part, these efforts haveprincipally involved the synthesis and testing of various new andheretofore unavailable organic compounds, particularly in the area ofthe sulfonylureas. However, in the search for still newer and moreimproved oral hypoglycemic agents, far less is known about the activityof various heterocyclic sulfonylureas like4-substituted-1-piperidinesulfonylureas and their derivatives. Forinstance, J. M. McManus et al. in the Journal of Medicinal Chemistry,Vol. 8, p. 766 (1965) report on several cyclicsulfamylureas that areactive, but none of these compounds possess any outstanding clinicaladvantages over that of either chlorpropamide or tolbutamide when usedin this connection.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has now been rathersurprisingly found that certain novel 1-piperidinesulfonylureas (i.e.,sulfamylureas) derived from a pyrimidine monocarboxylic acid areextremely useful when employed as oral hypoglycemic agents for thetreatment of diabetic subjects. The novel sulfamylurea compounds of thisinvention are all selected from the group consisting of1-piperidinesulfonylureas of the formula: ##STR1## and the base saltsthereof with pharmacologically acceptable cations, wherein R and R₁ areeach alkyl having from one to three carbon atoms, and R₂ is a memberselected from the group consisting ofbicyclo[2.2.1]hept-5-en-2-yl-endo-methyl,bicyclo[2.2.1]hept-2-yl-endo-methyl,7-oxabicyclo[2.2.1]hept-2-yl-endo-methyl, 1-adamantyl and cycloalkylhaving from five to eight carbon atoms. These compounds are all usefulin lowering blood sugar levels when administered by the oral route ofadministration.

Of especial interest in this connection are such typical and preferredmember compounds of the invention as1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea,1-(bicyclo[2.2.1]hept-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea,1-(7-oxabicyclo[2.2.1]hept-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea,1-(1-adamantyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea,1-cyclohexyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}ureaand1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl-3-{4-[2-(1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea,and their corresponding sodium salts. These particular compounds are allhighly potent as regards their hypoglycemic activity.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the process employed for preparing the novelcompounds of this invention, an appropriately substituted sulfamidecompound of the formula: ##STR2## is reacted with an organic isocyanatereagent of the formula R₂ NCO wherein R₂ corresponds to the previouslydefined 1-substituent on the urea moiety of the desired final product.In this way, the corresponding 1-piperidinesulfonylurea compound isformed where R and R₁ on the pyrimidine moiety are each defined aspreviously indicated. This particular reaction is normally conducted ina basic solvent medium, most desirably employing an aprotic organicsolvent such as tetrahydrofuran, dimethylsulfoxide or dimethylformamideand preferably using a slight excess in moles of a base, liketriethylamine or sodium hydride in mineral oil, etc. Many of theaforesaid isocyanate reagents (R₂ NCO) are either known compounds orelse they can easily be prepared, using methods well-known to thoseskilled in the art starting from readily available materials. Inpractice, it is usually preferable to employ at least about a molarequivalent of the isocyanate reagent in the aforesaid reaction of thepresent invention, with best results often being achieved by using aslight excess of same. Any temperature below that of reflux may be usedin order to effect the reaction, which normally requires a time periodof anywhere from several minutes up to about 24 hours depending, ofcourse, upon the particular 1-piperidinesulfonylurea being prepared aswell as the actual temperature of the reaction. Upon completion of thisstep, the product is easily isolated from the spent mixture in a mostconventional fashion, e.g., by pouring same into an excess of anhydrousdiethyl ether, whereby the desired 1-piperidinesulfonylurea readilyprecipitates in salt form from said mixture and is subsequentlycollected by such means as suction filtration and the like. Conversionto the free acidic compound then follows in due course in accordancewith the classical methods of organic chemistry.

Another method for preparing the subject compounds of this inventioninvolves reacting a 1-piperidinesulfamide in the form of an alkali metalor alkaline-earth metal salt (either employed as such or else formed insitu) with an appropriate 1,1,3-trisubstituted urea of the formula (R')₂NCONHR₂, wherein R' is an aryl group such as phenyl, p-chlorophenyl,p-bromophenyl, p-nitrophenyl, p-acetylaminophenyl, p-tolyl, p-anisyl,α-naphthyl, β-naphthyl, and the like. This reaction is preferablycarried out in the presence of a neutral polar organic solvent medium.Typical organic solvents for use in this connection include theN,N-dialkyl lower alkanoamides like dimethylformamide,dimethylacetamide, diethylformamide and diethylacetamide, as well aslower dialkyl sulfoxides such as dimethyl sulfoxide, diethyl sulfoxideand di-n-propyl sulfoxide, etc. It is desirable that the aforesaidsolvent for this reaction be present in sufficient amount to dissolveeach of the previously mentioned starting materials. In general, thereaction is conducted at a temperature that is in the range of fromabout 20° C. up to about 150° C. for a period of about 0.5 to about 24hours. The relative amounts of reagents employed are such that the molarratio of 1-piperidinesulfamide to the 1,1-diaryl-3-(monosubstituted)ureais most desirably in the preferred range of from about 1:1 to about 1:2,respectively. Recovery of the desired product from the reaction mixtureis then achieved by first diluting the reaction solution with water andthen adjusting if necessary the pH of the resulting solution to a valueof at least about 8.0, followed by subsequent extraction of the basicaqueous solution with any water-immiscible organic solvent in order toremove the diarylamine byproduct of formula (R')₂ NH as well as minoramounts of unreacted or excess starting material that might possibly bepresent at this stage. Isolation of the desired 1-piperidinesulfonylureafrom the basic aqueous layer then follows in due course, viz., by addinga sufficient amount of a dilute aqueous acid solution to causeprecipitation of the desired sulfamylurea to occur.

The two major type starting materials required for this reaction, viz.,the 1-piperidinesulfamides and the 1,1-diaryl-3-(monosubstituted)ureas,are both readily prepared by those skilled in the art in accordance withthe conventional methods of organic chemistry. For instance, the1-piperidinesulfamides, which are novel compounds and are also used asstarting materials in the previously described isocyanate method, aresuitably obtained by using classical methods of synthesis starting fromthe known 4-(2-aminoethyl)pyridine and proceeding in accordance withstandard organic procedure as hereinafter described in the experimentalsection of this specification in some detail (see Preparations A-F andExamples I-III). The 1,1-diaryl-3-(monosubstituted)-ureas, on the otherhand, are all readily prepared from common organic reagents by employingstandard procedures well known in the art, e.g., the desired1,1,3-trisubstituted urea may be prepared from the correspondingdisubstituted carbamyl chloride [(R')₂ NCOCl] and the appropriate amine(R₂ BH₂) in accordance with the general procedure of J. F. L. Reudler,as described in Recueil des Travaux Chimiques des Pays-Bas, Vol. 33, p.64 (1914 ).

The chemical bases which are used as reagents in this invention toprepare the aforementioned pharmaceutically acceptable base salts arethose which form non-toxic salts with the many herein described acidic1-piperidinesulfonylureas, such as1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1.3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-4-carboxamido)ethyl]-1-piperidinesulfonyl}urea,for example. These particular non-toxic base salts are of such naturethat their cations are said to be essentially non-toxic in characterover the wide range of dosage administered. Examples of such cationsinclude those of sodium, potassium, calcium and magnesium, etc. Thesesalts can easily be prepared by simply treating the aforementioned1-piperidinesulfonylureas with an aqueous solution of the desiredpharmacologically acceptable cations, and then evaporating the resultingsolution to dryness while preferably being placed under reducedpressure. Alternatively, they may also be prepared by mixing loweralkanolic solutions of the said acidic compounds and the desired alkalimetal alkoxide together, and then evaporating the resulting solution inthe same manner as before. In either case, stoichiometric amounts ofreagents must be employed in order to ensure completeness of reactionand maximum production of yields with respect to the desired finalproduct.

As previously indicated, the 1-piperidinesulfonylurea compounds of thisinvention are all readily adapted to therapeutic use as oralhypoglycemic agents, in view of their ability to lower the blood sugarlevels of diabetic and non-diabetic subjects to a statisticallysignificant degree. For instance,1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea(as the sodium salt), a typical and preferred agent of the presentinvention, has been found to consistently lower blood sugar levels inthe normal fasted rat (as well as in fed rats and dogs) to astatistically significant degree when given by the intraperitoneal routeof administration at dose levels ranging from 1.0 mg./kg. to 15 mg./kg.,respectively, without showing any substantial signs of toxic sideeffects. The other compounds of this invention also cause similarresults. Furthermore, all the herein described compounds of thisinvention can be administered orally, for the present purposes at hand,without causing any significant untoward pharmacological side reactionsto occur in the subject to whom they are so administered. In general,these compounds are ordinarily administered at dosage levels rangingfrom about 0.1 mg. to about 2.5 mg. per kg. of body weight per day,although variations will necessarily occur depending upon the conditionand individual response of the subject being treated and the particulartype of oral formulation chosen.

In connection with the use of the 1-piperidinesulfonylurea compounds ofthis invention for the treatment of diabetic subjects, it is to be notedthat they may be administered either alone or in combination withpharmaceutically acceptable carriers and that such administration can becarried out in both single and multiple dosages. More particularly, thenovel compounds of the invention can be administered in a wide varietyof different dosage forms, i.e., they may be combined with variouspharmaceutically acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, powders, aqueous suspension,elixirs, syrups and the like. Such carriers include solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents,etc. Moreover, such oral pharmaceutical compositions can be suitablysweetened and/or flavored by means of various agents of the typecommonly employed for just such a purpose. In general, thetherapeutically-effective compounds of this invention are present insuch dosage forms at concentration levels ranging from about 0.5% toabout 90% by weight of the total composition, i.e., in amounts which aresufficient to provide the desired unit dosage.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, gelatin and acacia. Additionally, lubricatingagents such as magnesium stearate, sodium lauryl sulfate and talc areoften very useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection would alsoinclude the high molecular weight polyethylene glycols. When aqueoussuspensions and/or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouslike combinations thereof.

The activity of the compounds of the present invention, as hypoglycemicagents, is determined by their ability to lower blood sugar levels inthe normal fasted rat when tested therein for such purposes according tothe procedure described by W. S. Hoffman, as reported in the Journal ofBiological Chemistry, Vol. 120, p. 51 (1937). The latter method measuresdirectly the amount of glucose in the blood at any given time and fromthis, the maximum percent decrease in blood sugar can be readilycalculated and reported as hypoglycemic activity per se. In this way,the present 1-piperidinesulfonylurea compounds are shown to markedlyreduce the blood sugar levels of non-anesthetized rats when administeredto them at dose levels as low as 1.0 mg./kg.

PREPARATION A

To a rapidly-stirred solution consisting of 148.1 g. (1.0 mole) ofphthalic anhydride dissolved in 1000 ml. of xylene and also containing13 ml. of triethylamine, there was slowly added in a dropwise manner122.1 g. (1.0 mole) of 4-(2-aminoethyl)pyridine [L. E. Brady et al.,Journal of Organic Chemistry, Vol. 26, p. 4758 (1961)] dissolved in 1000ml. of xylene. The reaction was slightly exothermic in nature and aheavy orange-yellow gum was observed to precipitate from the stirredsystem toward the end of the addition step. Upon completion of theaddition, the resulting reaction mixture was refluxed for a period ofapproximately two hours (using a Dean-Stark trap to remove the watertherefrom) and there was thus obtained a completely homogeneous yellowliquid. The latter liquid was then decanted while still hot into a2-liter Erlenmeyer Flask and slowly allowed to crystallized on coolingto room temperature (˜25° C.). In this manner, there were ultimatelyobtained 209 g. (83%) of crystalline 4-(2-phthalimidoethyl)pyridine inthe form of a white solid material melting at 155°-157° C.

Anal. Calcd. for C₁₅ H₁₂ N₂ O₂ : C, 71.41; H, 4.80; N, 11.11. Found: C,71.55; H, 4.91; N, 10.75.

A 15-gal. autoclave was charged with 1.8 kg. (7.13 moles) of4-(2-phthalimidoethyl)pyridine, 10.62 gal. of anhydrous methanolsaturated with dry hydrogen chloride gas and 72.2 g. of platinum oxidecatalyst. The autoclave and its contents were then placed under 200p.s.i. pressure of hydrogen, while at 50° C. and held at that pointuntil 95% of the theoretical hydrogen uptake was complete (this requiredapproximately 4.33 hours). At the end of this time, the reaction mixturewas cooled to 24° C., vented and then purged with nitrogen. Afterremoval of the catalyst by means of filtration, the resulting filtratewas concentrated in vacuo to a final volume of ca. 3.0 liters and thesolid product, which had precipitated from the residual liquid duringthe course of the concentration step, was then recovered by means ofcollecting same on a filter funnel with the aid of suction filtration.Upon washing with isopropanol and air-drying to constant weight, therewas obtained 1070 g. (51%) of crystalline4-(2-phthalimidoethyl)piperidine hydrochloride in the form of a purewhite solid (m.p. 235°-242° C.). Recrystallization from ethanol-diethylether then raised the melting point to 240°-242° C. (analytical sample).

Anal. Calcd. for C₁₅ H₁₈ N₂ O₂.HCl: C, 61.07; H, 6.49: N, 9.50. Found:C, 60.79; H, 6.37; N, 9.43.

A 12-liter three-necked, round-bottomed flask was charged with 1700 g.(5.69 mole) of 4-(2-phthalimidoethyl)piperidine hydrochloride, 552 g.(5.69 mole) of sulfamide and 5.8 liters of pyridine. The resultingreaction mixture was then stirred under the reflux conditions for aperiod of 24 hours and finally cooled to room temperature (˜25° C.). Thecooled mixture was next poured into an ice-water mixture (36 liters) andstirred for an additional period of 30 minutes. At this point, theprecipitated product was collected by means of suction filtration,washed with 5.0 liters of 0.1N hydrochloric acid, then with 15 liters ofwater and finally with 3.0 liters of cold ethanol. After air-drying toconstant weight, there was obtained a 1326 g. (71%) yield of pure4-(2-phthalimidoethyl)-1-piperidinesulfonamide, m.p. 195°-197° C.Recrystallization from ethanol then gave the analytical sample as awhite solid material (m.p. 202°-203° C.).

A 1-liter round-bottomed flask was charged with 28.4 g. (0.084 mole) of4-(2-phthalimidoethyl)-1-piperidinesulfonamide, 2.7 g. (0.084 mole) ofanhydrous hydrazine and 250 ml. of methanol. The resulting whitesuspension was stirred and then refluxed for a period of 90 minutes,followed by removal of the most of the methanol via fractionaldistillation. At this point, the reaction mixture was observed to be ahomogeneous yellow solution. Concentrated hydrochloric acid (350 ml.)was then added, and the resulting mixture was refluxed for an additionalperiod of three hours before being cooled to room temperature. Theinsoluble byproduct, which appeared at this point as a precipitate, wasthen removed by means of suction filtration and the resulting filtratewas thereafter evaporated to near dryness while under reduced pressureto give a white solid material as the final residual product. The latterwas subsequently triturated with hot acetone, filtered and air dried toconstant weight to afford 18.5 g. (91%) of pure4-(2-aminoethyl)-1-piperidinesulfonamide hydrochloride, m.p. 188°-192°C. Recrystallization from ethanol then gave the analytical sample (m.p.195°-197° C.).

Anal. Calcd. for C₇ H₁₇ N₃ O₂ S.HCl: C, 34.49; H, 7.44; N, 17.24. Found:C, 34.56; H, 7.45; N, 17.24.

PREPARATION B

A suspension of 9.2 g. (0.05 mole) of1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylic acid[C. W. Whitehead, Journal of the American Chemical Society, Vol. 74, p.4267 (1952)] in 50 ml. of carbon tetrachloride and 70 ml. of thionylchloride was heated on a steam bath for a period of 45 minutes. At theend of this time, the clear solution so obtained was concentrated invacuo and excess thionyl chloride was then removed by adding 100 ml. ofbenzene to the solution and subsequently evaporating the resultingmixture to dryness while under reduced pressure. This particularpurification step was repeated again and there was ultimately obtainedpure 1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylicacid chloride in the form of a white crystalline residue, which was usedas such in the next reaction step without any further purification beingnecessary. The yield of the acid chloride product was nearlyquantitative.

PREPARATION C

A suspension of 2.3 g. (0.01 mole) of1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylicacid [prepared according to the method of C. W. Whitehead, Journal ofthe American Chemical Society, Vol. 74, p. 4267 (1952)] in 10 ml. ofcarbon tetrachloride and 10 ml. of thionyl chloride was heated on asteam bath until evolution of both hydrogen chloride and sulfur dioxidegas subsided. Removal of the solvent and excess thionyl chloride fromthe mixture was then accomplished by concentrating same in vacuo,followed by the addition of 50 ml. of benzene to the residue in order toremove any remaining traces of thionyl chloride. The resulting mixturewas then evaporated to dryness while under reduced pressure and afterrepeating the entire purification procedure three times, there wasultimately obtained pure1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylicacid chloride in the form of a pale yellow crystalline residue. Thelatter material was used in the next reaction step without any furtherpurification being necessary. The yield of said acid chloride productwas quantitative.

PREPARATION D

The procedure described in Preparations B-C is repeated here to preparethe following1,3-dialkyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylic acidchlorides, starting from the corresponding acid in each case:

1-methyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylicacid chloride

1-methyl-3-isopropyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylicacid chloride

1-ethyl-3-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylicacid chloride

1,3-diethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylic acidchloride

1-ethyl-3-n-propyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylicacid chlorde

1-isopropyl-3-methyl-1,2,3,4-tetrahydropyrimidne-2,4-dione-5-carboxylicacid chloride

1,3-di-n-propyl-1,2,3,4-tetrahydropyrimidne-2,4-dione-5-carboxylic acidchloride

PREPARATION E

A 500 ml. three-necked, round bottomed flask was charged with 14.6 g.(0.119 mole) of endo-2-aminomethylbicyclo[2.2.1]hept-5-ene [P. Wilder etal., Journal of Organic Chemistry, Vol. 30, p. 3078 (1965)], 18.0 g.(0.178 mole) of triethylamine and 100 ml. of tetrahydrofuran. Themixture was then rapidly cooled and stirred in an ice bath, while asolution consisting of 27.4 g. (0.119 mole) of N,N-diphenylcarbamoylchloride dissolved in 100 ml. of tetrahydrofuran was slowly addedthereto in a dropwise manner. After the addition was complete, thereaction mixture was stirred at room temperature (˜25° C.) for a periodof one hour and the resulting solution was then concentrated in vacuo(to approximately one-third of its original volume) to remove most ofthe tetrahydrofuran. On cooling, there was obtained a crystallineprecipitate, which was subsequently collected by means of suctionfiltration and thereafter suspended in 250 ml. of 1N aqueoushydrochloric acid. Extraction of the latter aqueous solution with three200-ml. portions of chloroform, followed by drying of the combinedorganic extracts then gave a clear organic solution upon filtration.After evaporating the clear filtrate to near dryness while under reducedpressure, there was ultimately obtained a heavy viscous oil, whichsubsequently crystallized on trituration with n-hexane.Recrystallization of this latter material from diethyl ether/n-hexanethen gave pure1,1-diphenyl-3-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)urea, m.p.129°-130° C. The analytical sample was a crystalline white solid.

Anal. Calcd. for C₂₁ H₂₂ N₂ O: C, 79.21: H, 6.96; N, 8.80. Found: C,79.19; H, 7.05; N, 8.93.

PREPARATION F

A 3-liter round-bottomed flask was charged with 212 g. (4.0 moles) ofacrylonitrile, 272 g. (4.0 moles) of furan and 50 mg. of hydroquinoneall dissolved in a total of one liter of dry benzene. Stirring was thencommenced, while a solution consisting of 55 ml. (0.5 mole) of titaniumtetrachloride dissolved in 500 ml. of benzene was added at such a ratethat the temperature did not exceed 35° C. The resulting mixture wasthen stirred at room temperature (˜25° C.) for a period of five days inorder to complete the reaction, followed by treatment with 500 ml. of0.5N hydrochloric acid. After filtering the acidified mixture, thebenzene layer was collected and subsequently saved, while the aqueouslayer was extracted anew with a fresh portion of benzene. At this point,the organic layers were combined, washed with water and then dried overanhydrous magnesium sulfate. After removal of the drying agent by meansof suction filtration and the organic solvent by means of evaporationunder reduced pressure, there was obtained 156.3 g. (32%) of7-oxabicyclo[2.2.1]hept-5-en-2-ylnitrile in the form of a crude mixtureof endo- and exo-isomers.

The above crude mixture (130 g.) was then hydrogenated in 1000 ml. ofacetone at 50 p.s.i. pressure, using 2 g. of palladium-on-barium sulfateas catalyst. After removal of the catalyst by means of suctionfiltration and the solvent by means of evaporation under reducedpressure, there was obtained a residual liquid which on fractionaldistillation gave 55.5 g. (42%) of pureendo-7-oxabicyclo[2.2.1]hept-2-ylnitrile (b.p. 45° C./0.1 mm. Hg) and37.9 g. (29%) of pure exo-7-oxabicyclo[2.2.1]hept-2-ylnitrile (b.p. 48°C./0.02 mm.Hg) plus 14.7 g. (11%) of an endo/exo mixture.

Anal. Calcd. for C₇ H₉ NO: C, 68.27; H, 7.37; N, 11.37. Found: (endo):C, 67.96; H, 7.21; N, 11.37. (exo): C, 68.32; H, 7.42; N, 11.64.

To a well-stirred solution consisting of 54.3 g. (9.44 mole) ofendo-7-oxabicyclo[2.2.1]hept-2-ylnitrile dissolved in 500 ml. ofmethanol, there were added 24 ml. of a slurry of Raney nickel inmethanol, followed by the dropwise addition of 33.2 g. (0.88 mole) ofsodium borohydride dissolved in 110 ml. of 4N aqueous sodium hydroxide.The latter step was carried out with the aid of external cooling so asto keep the temperature of the reaction mixture within the 40°-50° C.range. After the addition was complete (and this required approximately25 minutes), the mixture was further stirred at ambient temperatures(i.e., without cooling) for a period of 20 minutes, at which point nofurther gas evolution could be detected. The spent reaction mixture wasthen filtered to remove solid impurities, and the resulting filtratethereafter concentrated in vacuo to afford a residue that wassubsequently suspended in 500 ml. of 1N aqueous sodium hydroxide. Afterextracting the latter basic aqueous solution three times withchloroform, the chloroform extracts were combined, dried over anhydrousmagnesium sulfate and thereafter evaporated to constant volume whileunder reduced pressure to give 55.5 g. (100%) ofendo-7-oxabicyclo[2.2.1]hept-2-ylmethylamine (b.p. 90° C./10 mm. Hg.),which was used as such in the next reaction step without any furtherpurification being necessary.

The procedure described in Preparation E was now repeated to prepare the1,1-diphenyl-3-(monosubstituted)urea compound except thatendo-7-oxabicyclo[2.2.1]hept-2-ylmethylamine obtained as described abovewas the appropriate amine starting material employed in place ofendo-2-aminomethylbicyclo[2.2.1]hept-5-ene, again using the same molarproportions as before. In this particular case, the corresponding finalproduct thus obtained was1,1-diphenyl-3-(7-oxabicyclo[2.2.1]hept-2-yl-endo-methyl)-urea, m.p.109°-111° C.

Anal. Calcd. for C₂₀ H₂₂ N₂ O₂ : C, 74.49; H, 6.89; N, 8.68. Found: C,74.28; H, 6.93; N, 8.61.

EXAMPLE I

To a mixture of 12.1 g. (0.05 mole) of4-(2-aminoethyl)-1-piperidinesulfonamide hydrochloride and 10.2 g. (0.10mole) of triethylamine in 100 ml. of dry tetrahydrofuran, there wasadded the product of Preparation B (viz.,1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylic acidchloride) suspended in 50 ml. of tetrahydrofuran. The reaction mixturewas then stirred at ambient temperatures for a period of approximately16 hours. At the end of this time, the precipitated solids which formedwere subsequently recovered by means of suction filtration andthereafter thoroughly digested with 200 ml. of water. The insolubleproduct was then collected again on the filter funnel and air-dried toconstant weight, followed by recrystallization from 200 ml. of acetoneto give 17 g. (94%) of pure4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonamide,m.p. 201°-202° C.

Anal. Calcd. for C₁₃ H₂₃ N₅ O₅ S: C, 45.03; H, 6.14; N, 19.38. Found: C,45.33; H, 6.14; N, 19.45.

EXAMPLE II

To a mixture of 2.4 g. (0.01 mole) of4-(2-aminoethyl)-1-piperidinesulfonamide hydrochloride and 2.0 g. (0.02mole) of triethylamine in 25 ml. of dry tetrahydrofuran, there was addedthe product of Preparation C (viz.,1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylicacid chloride) suspended in 25 ml. of dry tetrahydrofuran. The reactionmixture was then stirred at ambient temperatures for a period ofapproximately 16 hours. At the end of this time, the crystallineprecipitate of triethylamine hydrochloride was removed by suctionfiltration and the resulting filtrate was thereafter evaporated todryness under reduced pressure to give 4.0 g. of crude4-[2-(1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonamidein the form of a yellow colored gum. The latter material was thenrecrystallized from acetonitrile and there was ultimately obtained(after three recrystallizations) 2.0 g. of pure product, viz.,4-[2-(1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonamidein the form of white needles melting at 164°-165.5° C. The yield of pureproduct amounted to 47%.

Anal. Calcd. for C₁₇ H₂₃ N₅ O₅ S: C, 49.14; H, 7.03; N, 16.86. Found: C,49.01; H, 6.89; N, 16.89.

EXAMPLE III

The procedure described in Examples I-II is repeated to prepare thefollowing 1-piperidinesulfamides by simply using the appropriate1,3-dialkyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxylic acidchloride as the requisite starting material of choice in each instance:

    ______________________________________                                         ##STR3##                                                                     R                     R.sub.1                                                 ______________________________________                                        C.sub.2 H.sub.5       CH.sub.3                                                iso-C.sub.3 H.sub.7   CH.sub.3                                                CH.sub.3              C.sub.2 H.sub.5                                         C.sub.2 H.sub.5       C.sub.2 H.sub.5                                         n-C.sub.3 H.sub.7     C.sub.2 H.sub.5                                         CH.sub.3              iso-C.sub.3 H.sub.7                                     n-C.sub.3 H.sub.7     n-C.sub.3 H.sub.7                                       ______________________________________                                    

example iv

a mixture of 2.8 g. (0.0075 mole) of4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonamide,2.4 g. (0.0075 mole) of1,1-diphenyl-3-bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)urea and 0.34 g.(0.0075 mole) of 56% sodium hydride (in mineral oil) in 15 ml. of dryN,N-dimethylformamide was heated to 70° C. for a period of one hour. Theclear solution so obtained was then cooled and subsequently poured into200 ml. of diethyl ether, followed by recovery of the resultingcrystalline precipitate via suction filtration. The filter cake was thenwashed well with diethyl ether and thereafter dissolved in 50 ml. ofwater. Upon acidification with 10 ml. of 6N hydrochloric acid andextraction into chloroform (three-50 ml. portions were required),followed by decolorization with charcoal and drying over anhydrousmagnesium sulfate, there was finally obtained a clear chloroformsolution of the desired product. Evaporation of the latter solution tonear dryness while under reduced pressure then gave a crystallineresidue, which was subsequently recrystallized from 350 ml. ofacetonitrile to give 2.2 g. (57%) of pure1-(bicyclo-[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea,m.p. 216°-217° C.

Anal. Calcd. for C₂₃ H₃₄ N₆ O₆ S: C, 52.86; H, 6.65; N, 16.08. Found: C,52.74; H, 6.50; N, 16.65.

EXAMPLE V

A mixture of 1.0 g. (0.002 mole) of1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}ureaand 0.20 g. of 5% palladium-on-carbon catalyst in 300 ml. oftetrahydrofuran was hydrogenated on a Parr shaker at 40 p.s.i. pressureuntil no further hydrogen uptake could be detected. The catalyst wasthen separated from the mixture by means of filtration and the resultingfiltrate thereafter evaporated to dryness under reduced pressure. Inthis manner, there was obtained a crude residual product which afterrecrystallization from acetonitrile afforded pure1-(bicyclo[2.2.1]hept-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea(m.p. 211.5°-212.5° C.) in 74% yield.

Anal. Calcd. for C₂₃ H₃₆ N₆ O₆ S.O.5H₂ O C, 51.76; H, 6.99; N, 15.75.Found: C, 51.89; H, 6.71; N, 16.01.

EXAMPLE VI

A mixture consisting of 750 mg. (0.002 mole) of4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)-ethyl]-1-piperidinesulfonamide,280 mg. (0.002 mole) of cyclohexyl isocyanate and 90 mg. (0.002 mole) of56.6% sodium hydride (dispersed in mineral oil) in 10 ml. of dryN,N-dimethylformamide was stirred at ambient temperatures for a periodof 14 hours. At the end of this time, the mixture was poured into 300ml. of anhydrous diethyl ether and the white crystalline precipitatewhich formed at this point was subsequently recovered by means ofsuction filtration and washed well with fresh diethyl ether prior tobeing dissolved in 1N aqueous hydrochloric acid. The latter aqueoussolution was then extracted with chloroform and the chloroform extractsthereafter separated from the aqueous layer, washed well with water andthen finally with a saturated solution of aqueous sodium chloride. Afterdrying the chloroform solution over anhydrous magnesium sulfate,followed by decolorization with charcoal, there was ultimately obtaineda clear chloroform solution of the desired final product. Evaporation ofthe latter solution to near dryness while under reduced pressure thengave a white solid material, which afforded pure1-cyclohexyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea(m.p. 205°-207° C.) on recrystallization from acetonitrile-methanol. Theyield of pure product was 70% of the theoretical value.

Anal. Calcd. for C₂₁ H₃₄ N₆ O₆ S.0.5H₂ O: C, 49.69; H, 6.95; N, 16.56.Found: C, 49.44; H, 6.65; N, 16.58.

EXAMPLE VII

A mixture of 1.7 g. (0.004 mole) of4-[2-(1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonamide,1.6 g. (0.005 mole) of1,1-diphenyl-3-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)urea and 0.23g. (0.005 mole) of 56% sodium hydride (in mineral oil) in 20 ml. of dryN,N-dimethylformamide was heated at 65° C. for a period of 1.5 hours. Atthe end of this time, a homogenous yellow solution was obtained whichwas subsequently cooled and poured into 150 ml. of dry diethyl ether.The white crystalline solid which separated at this point was the crudesodium salt of1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea.Purification was then accomplished via recrystallization fromchloroform-ethyl acetate to give 0.94 g. of a white, hygroscopiccompound which melted at 143° C. with decomposition. The yield of pureproduct was 39.6% of the theoretical value.

Anal. Calcd. for C₂₆ H₃₉ N₆ O₆ SNa.2H₂ O: C, 50.06; H, 6.24; N, 13.48Found: C, 49.98; H, 6.42; N, 13.22.

EXAMPLE VIII

A mixture of 380 mg. (0.001 mole) of4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonamide,220 mg. (0.001 mole) of 1-adamantyl isocyanate and 310 mg. (0.002 mole)of anhydrous potassium carbonate in 30 ml. of acetone was refluxed for aperiod of 20 hours. At the end of this time, the spent reaction mixturewas cooled and the excess potassium carbonate subsequently removedtherefrom by means of suction filtration. The resulting filtrate wasthen slowly acidified with 1N aqueous hydrochloric acid causing a whiteprecipitate to form. The latter material was subsequently recovered bysuction filtration and thereafter recrystallized fromacetonitrile-methanol to afford 220 mg (38%) of pure1-(1-adamantyl)3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea,m.p. 224°-226° C.

Anal. Calcd. for C₂₅ H₃₈ N₆ O₆ S.H₂ O: C, 52.80; H, 7.09; H, 14.78.Found: C, 52.76; H, 6.43; N, 14.96.

EXAMPLE IX

A mixture consisting of 1.12 g. (0.003 mole) of4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonamide,1.35 g. (0.004 mole) of1,1-diphenyl-3-(7-oxabicyclo[2.2.1]hept-2-yl-endo-methyl)urea and 0.19g. (0.004 mole) of 56% sodium hydride (in mineral oil) in 10 ml. of dryN,N-dimethylformamide was stirred at ambient temperature for a period of18 hours. The resulting mixture was then poured into 200 ml. ofanhydrous diethyl ether to yield a white-colored gum that wassubsequently recovered by means of decantation and washed twice withfresh diethyl ether. The gum was then dissolved in 1N aqueoushydrochloric acid and the latter aqueous solution extracted withchloroform, followed by separation of the organic layer and drying overanhydrous magnesium sulfate. After decolorizing the organic (chloroform)solution with charcoal and filtering, there was obtained a clearsolution which was subsequently evaporated to near dryness while underreduced pressure to afford a pale yellow-colored oil. Crystallization ofthe latter material from acetonitrile then gave (after threerecrystallizations) pure1-(7-oxabicyclo[2.2.1]hept-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}ureain the form of white crystals melting at 217°-218° C. The yield of pureproduct was 20% of the theoretical value.

Anal. Calcd. for C₂₂ H₃₄ N₆ O₇ S: C, 50.18; H, 6.51; N, 15.96. Found: C,49.97; H, 6.51; N, 15.66.

EXAMPLE X

The following 1-piperidinesulfonylureas are prepared by employing theprocedures described in the previous sulfamylurea examples (viz.,Examples IV-IX), starting from the corresponding sulfamide and theappropriate organic isocyanate or 1,1-diphenyl-3-substituted urea ineach instance:

    ______________________________________                                         ##STR4##                                                                     R      R.sub.1  R.sub.2                                                       ______________________________________                                        CH.sub.3                                                                             CH.sub.3 cyclopentyl                                                   C.sub.2 H.sub.5                                                                      n-C.sub.3 H.sub.7                                                                      cyclohexyl                                                    C.sub.2 H.sub.5                                                                      CH.sub.3 cycloheptyl                                                   iso-C.sub.3 H.sub.7                                                                  CH.sub.3 cyclooctyl                                                    CH.sub.3                                                                             C.sub.2 H.sub.5                                                                        bicyclo[2 . 2 . 1]hept-5-en-2-yl-endo-methyl                  C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        bicyclo[2 . 2 . 1]hept-2-yl-endo-methyl                       n-C.sub.3 H.sub.7                                                                    C.sub.2 H.sub.5                                                                        7-oxabicyclo[2 . 2 . 1]hept-2-yl-endo-methyl                  CH.sub.3                                                                             iso-C.sub.3 H.sub.7                                                                    1-adamantyl                                                   n-C.sub.3 H.sub.7                                                                    n-C.sub.3 H.sub.7                                                                      cyclopentyl                                                   CH.sub.3                                                                             CH.sub.3 cycloheptyl                                                   C.sub.2 H.sub.5                                                                      n-C.sub.3 H.sub.7                                                                      cyclooctyl                                                    n-C.sub.3 H.sub.7                                                                    n-C.sub.3 H.sub.7                                                                      bicyclo[2 . 2 . 1]hept-5-en-2-yl-endo-methyl                  n-C.sub.3 H.sub.7                                                                    n-C.sub.3 H.sub.7                                                                      bicyclo[2 . 2 . 1]hept-2-yl-endo-methyl                       CH.sub.3                                                                             C.sub.2 H.sub.5                                                                        7-oxabicyclo[2 . 2 . 1]hept-2-yl-endo-methyl                  C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        1-adamantyl                                                   n-C.sub.3 H.sub.7                                                                    C.sub.2 H.sub.5                                                                        cyclopentyl                                                   n-C.sub.3 H.sub.7                                                                    n-C.sub.3 H.sub.7                                                                      cyclohexyl                                                    n-C.sub.3 H.sub.7                                                                    n-C.sub.3 H.sub.7                                                                      cycloheptyl                                                   CH.sub.3                                                                             CH.sub.3 cyclooctyl                                                    C.sub.2 H.sub.5                                                                      n-C.sub.3 H.sub.7                                                                      bicyclo[2 . 2 . 1]hept-5-en-2-yl-endo-methyl                  CH.sub.3                                                                             iso-C.sub.3 H.sub.7                                                                    bicyclo[2 . 2 . 1]hept-2-yl-endo-methyl                       iso-C.sub.3 H.sub.7                                                                  CH.sub.3 7-oxabicyclo[2 . 2 . 1]hept-2-yl-endo-methyl                  n-C.sub.3 H.sub.7                                                                    n-C.sub.3 H.sub.7                                                                      1-adamantyl                                                   C.sub.2 H.sub.5                                                                      n-C.sub.3 H.sub.7                                                                      cyclopentyl                                                   CH.sub.3                                                                             iso-C.sub.3 H.sub.7                                                                    cyclohexyl                                                    n-C.sub.3 H.sub.7                                                                    n-C.sub.3 H.sub.7                                                                      cyclooctyl                                                    ______________________________________                                    

EXAMPLE XI

A solution consisting of 338.4 g. (0.72 mole) of1-(bicyclo-[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}ureadissolved in 2.0 liters of methanol was treated at 0° C. with 38.9 g.(0.72 mole) of sodium methoxide divided into five separate portions. Thereaction mixture was then concentrated in vacuo and the resultingresidue thereafter recrystallized from 7.0 liters of acetonitrile togive a nearly quantitative yield of product, viz., the sodium salt of1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea,m.p. 153°-190° C.

Anal. Calcd. for C₂₃ H₃₃ N₆ O₆ SNa.1.5H₂ O: C, 48.32; H, 5.82; N, 14.72.Found: C, 48.40; H, 5.73; N, 14.52.

EXAMPLE XII

The sodium salt of1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}ureais prepared by dissolving said compound in anhydrous methanol and thenadding said solution to another methanolic solution which contains anequivalent amount in moles of sodium methoxide. Upon subsequentevaporation of the solvent therefrom via freeze-drying, there isobtained the desired alkali metal salt in the form of an amorphous solidpower which is freely soluble in water.

In like manner, the potassium and lithium salts are also similarlyprepared, as are the alkali metal salts of all the other acidic1-piperidinesulfonylureas of this invention which are reported in theprevious examples.

EXAMPLE XIII

The calcium salt of1-cyclohexyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}ureais prepared by dissolving said compound in water containing anequivalent amount in moles of calcium hydroxide and then freeze-dryingthe mixture. The corresponding magnesium salt is also prepared in likemanner, as are all the other alkaline-earth metal salts not only of thisparticular compound, but also of those acidic 1-piperidinesulfonyl-ureaspreviously described in Examples IV-V and VII-IX, respectively.

EXAMPLE XIV

A dry solid pharmaceutical composition is prepared by blending thefollowing materials together in the proportions by weight specifiedbelow:

    ______________________________________                                        1-(Bicyclo[2 . 2 . 1]hept-5-en-2-yl-endo-methyl)-3-                            {4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-                         dione-5-carboxamido)ethyl]-1-                                                 piperidinesulfonyl}urea     50                                               Sodium citrate               25                                               Alginic acid                 10                                               Polyvinylpyrrolidone         110                                              Magnesium stearate           5                                                ______________________________________                                    

After the dried composition is thoroughly blended, tablets are punchedfrom the resulting mixture, each tablet being of such size that itcontains 75 mg. of the active ingredient. Other tablets are alsoprepared in a similar fashion containing 5, 10, 25 and 50 mg. of theactive ingredient, respectively, by merely using the appropriate amountof the 1-piperidinesulfonylurea in each case.

EXAMPLE XV

A dry solid pharmaceutial composition is prepared by combining thefollowing materials together in the proportions by weight indicatedbelow:

    ______________________________________                                        1-Cyclohexyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydro-                         pyrimidine-2,4-dione-5-carboxamido)ethyl]-                                    1-piperidinesulfonyl}urea   50                                               Calcium carbonate            20                                               Polyethylene glycol, average molecular weight, 4000                                                        30                                               ______________________________________                                    

The dried solid mixture so prepared is then thoroughly agitated so as toobtain a powdered product that is completely uniform in every respect.Soft elastic and hard-filled gelatin capsule containing thispharmaceutical composition are then prepared, employing a sufficientquantity of material in each instance so as to provide each capsule with125 mg. of the active ingredient.

EXAMPLE XVI

The 1-piperidinesulfonylurea final products of Examples IV-IX weretested for hypoglycemic activity in groups of six male albino rats (eachweighing approximately 190-240 g.) of the Sprague-Dawley strain. Noanesthetic was used in this study. The rats were fasted forapproximately 18-24 hours prior to administration, a blood sample wasthen taken from the tail vein of each animal and the test compound wasadministered intraperitoneally (while in solution as the sodium salt in0.9% saline) at dose levels of 15, 5.0 and 1.0 mg./kg., respectively.Additional blood samples were then take at 1, 2 and 4 hour intervalsafter administration of the drug. The samples were immediately diluted1:10 (by volume) with 1.0% heparin in 0.9% saline. Blood glucose wasdetermined by adapting the method of W. S. Hoffman [Journal ofBiological Chemistry, Vol. 120, p. 51 (1937)] to the Autoanalyzerinstrument produced by Technicon Instruments Corporation of Chauncey,N.Y. On this basis, the maximum percent decrease in blood sugar wascalculated and reported as such (i.e., as hypoglycemic activity) for thevarious compounds listed in the table below:

    ______________________________________                                        1-Piperidine-  Hypoglycemic Activity (Max.% Fall)                             sulfonylurea   1.0mg./kg.                                                                              5.0mg./kg.                                                                              15mg./kg.                                  ______________________________________                                        Product of Example IV                                                                        5.5       21        --                                         Product of Example V                                                                         --        19        --                                         Product of Example VI                                                                        --        --        29                                         Product of Example VII                                                                       --        13        --                                         Product of Example VIII                                                                      --        19        --                                         Product of Example IX                                                                        --        --        13                                         ______________________________________                                    

What is claimed is:
 1. A method for lowering blood sugar in the treatment of a diabetic animal, which comprises orally administering to said animal an effective blood sugar lowering amount of a compound selected from a group consisting of 1-piperidinesulfonylureas of the formula: ##STR5## and the base salts thereof with pharmacologically acceptable cations, wherein R and R₁ are each alkyl having from one to three carbon atoms, and R₂ is a member selected from the group consisting of bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl, bicyclo[2.2.1]hept-2-yl-endo-methyl, 7-oxabicyclo[2.2.1]hept-2-yl-endo-methyl, 1-adamantyl and cycloalkyl having from five to eight carbon atoms.
 2. The method as claimed in claim 1 wherein the compound administered is 1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea.
 3. The method as claimed in claim 1 wherein the compound administered is 1-(bicyclo[2.2.1]hept-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea.
 4. The method as claimed in claim 1 wherein the compound administered is 1-(1-adamantyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboamido)ethyl]-1-piperidinesulfonyl}urea.
 5. The method as claimed in claim 1 wherein the compound administered is 1-cyclohexyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea.
 6. The method as claimed in claim 1 wherein the compound administered is 1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea.
 7. An oral hypoglycemic pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective blood sugar lowering amount of an oral hypoglycemic agent selected from the group consisting of 1-piperidinesulfonylureas of the formula: ##STR6## and the base salts thereof with pharmacologically acceptable cations, wherein R and R₁ are each alkyl having from one to three carbon atoms, and R₂ is a member selected from the group consisting of bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl, bicyclo[2.2.1]hept-2-yl-endo-methyl, 7-oxabicyclo[2.2.1]hept-2-yl-endo-methyl, 1-adamantyl and cycloalkyl having from five to eight carbon atoms.
 8. The composition according to claim 7 wherein the hypoglycemic agent is 1-(bicyclo[2.2.1]hept-5-en-2-yl-endomethyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea.
 9. The composition according to claim 7 wherein the hypoglycemic agent is 1-(bicyclo[2.2.1]hept-2-yl-endo-methyl)-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea.
 10. The composition according to claim 7 wherein the hypoglycemic agent is 1-(1-adamantyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea.
 11. The composition according to claim 7 wherein the hypoglycemic agent is 1-cyclohexyl-3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea.
 12. The composition according to claim 7 wherein the hypoglycemic agent is 1-(bicyclo[2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(1-n-propyl-3-ethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea. 